Pyridone derivatives and their use in the treatment, ameloriation or prevention of a viral disease

Abstract

The present invention relates to a compound having the general formula (II), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.

The invention claimed is: 
     
       1. A compound having the general formula (II), 
       
         
           
           
               
               
           
         
       
       wherein
 X 20  is NR 25 , N(R 25 )C(O), C(O)NR 25 , O, C(O), C(O)O, OC(O); N(R 25 )SO 2 , SO 2 N(R 25 ), S, SO, or SO 2 ; 
 R 20  is —H, a —C 1-6  alkyl group or a —C(O)—C 1-6  alkyl group; 
 R 21  is —H, a —C 1-6  alkyl group, or a —C 1-6  alkyl group which is substituted by one or more halogen atoms; 
 R 22  is —H, a —C 1-6  alkyl group, or a —C 1-6  alkyl group which is substituted by one or more halogen atoms; 
 or wherein R 21  and R 22  can be joined together to form a 3- to 7-membered carbo- or heterocyclic ring; 
 R 23  is —R 26 , or —X 20 —R 26 ; 
 R 24  is H, or a C 1-6  alkyl group; 
 R 25  is —H, -(optionally substituted C 1-6  alkyl), -(optionally substituted C 3-7  cycloalkyl), -(optionally substituted aryl), —C 1-4  alkyl-(optionally substituted C 3-7  cycloalkyl), or —C 1-4  alkyl-(optionally substituted aryl); 
 R 26  is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from 0, N and S and which contains at least one ring); 
 R 27  is —H, —C 1-6  alkyl, or —(CH 2 CH 2 O) r H; 
 R 28  is —H, or —C 1-6  alkyl; 
 R is independently selected from —C 1-6  alkyl, —C(O)—C 1-6  alkyl, —Hal, —CF 3 , —CN, —COOR 27 , —OR 27 , —(CH 2 ) q NR 27 R 28 , —C(O)—NR 27 R 28 , and —NR 27 —C(O)—C 1-6  alkyl; 
 q is 0 to 4; and 
 r is 1 to 3; 
 wherein the alkyl group, aryl group, hydrocarbon group and/or cycloalkyl group can be optionally substituted with one or more substituents R, 
 or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof. 
 
     
     
       2. The compound according to  claim 1 , wherein R 23  is —R 26 . 
     
     
       3. The compound according to  claim 1 , wherein R 23  is —X 20 —R 26  and X 20  is N(R 25 )SO 2 . 
     
     
       4. The compound according to  claim 1 , wherein R 21  and R 22  are —H. 
     
     
       5. The compound according to  claim 1 , wherein R 26  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein
 X is absent, CH 2 , NH, C(O)NH, S or O; 
 Y is CH 2 ; 
 Z is O or S; and 
 R is independently selected from —H, —C 1-6  alkyl, —CF 3 , -halogen, —CN, —OH, and —O—C 1-6  alkyl. 
 
     
     
       6. A pharmaceutical composition comprising:
 a compound according to  claim 1 , 
 and one or more pharmaceutically acceptable excipient(s) and/or carrier(s). 
 
     
     
       7. The pharmaceutical composition according to  claim 6 , which additionally comprises a further medicament selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (II); a neuramidase inhibitor; a M2 channel inhibitor; an alpha glucosidase inhibitor; a ligand of another influenza target; an antibiotic, an anti-inflammatory agent, a lipoxygenase inhibitor, an EP ligand, a bradykinin ligand, a cannabinoid ligand, and combinations thereof. 
     
     
       8. A compound according to  claim 1 , wherein the compound is for use in the treatment, of influenza. 
     
     
       9. A method of treating influenza, the method comprising administering to a patient in need thereof an effective amount of a compound according to  claim 1 . 
     
     
       10. The method according to  claim 9  further comprising adminstering an effective amount of at least one further medicament which is selected from the group consisting of a polymerase inhibitor which is different from the compound having the general formula (II); a neuramidase inhibitor; a M2 channel inhibitor; an alpha glucosidase inhibitor; a ligand of another influenza target; an antibiotic, an anti-inflammatory agent, a lipoxygenase inhibitor, an EP ligand, a bradykinin ligand, a cannabinoid ligand, and combinations thereof. 
     
     
       11. The compound according to  claim 1 , which exhibits an IC 50  of less than about 40 μM in an FRET endonuclease activity assay. 
     
     
       12. The method according to  claim 10 , wherein the further medicament is administered concurrently with, sequentially with or separately from the compound having the general formula (II). 
     
     
       13. The pharmaceutical composition of  claim 6 , wherein the composition is for use in the treatment of influenza.